Wnt proteins are a family of secreted polypeptides that act through a signaling pathway, which is known as the Wnt signaling pathway. Previously described members of the Wnt signalling pathway include the putative Wnt receptor, which is encoded by members of the frizzled gene family. Other members of the Wnt-signalling pathway include the transcription factor beta-catenin, the adenomatous polyposis coli (APC) polypeptide, presenilin (PS), GSK-3b, Protein Phosphatase 2A proteins, the kinases CamKII and PKC, glycogen synthase kinase 3, the Dishevelled (Dvl) protein, and cyclins D1 and c-myc. Transcription of these latter genes is reported to be associated with activation of the Wnt signaling pathway. Interactions between some members of the Wnt-signaling pathway have been described. For example, APC is phosphorylated by GSK-3b, binds to beta-catenin and facilitates its degradation.
Wnt proteins control cell processes via at least two pathways. One of these, known as the “canonical” Wnt signaling pathway, operates through the cytosolic stabilization of beta-catenin (Smalley M J and Dale T C, 1999). Stabilization is achieved by downregulating the activity of a beta-catenin turnover complex. In the second pathway, activation of the Wnt signaling pathway stimulates intracellular Ca2+ release and activates the kinases CamKII and PKC (Kuhl et al, Trends Genet 2000 July; 16(7):279-83).
Wnt signaling is involved in a variety of mammalian developmental processes, including cell proliferation, differentiation and epithelial-mesenchymal interactions (Smalley M J and Dale T C, Cancer Metastasis Rev 1999; 18(2):215-30). For example, Wnt signaling contributes to the development of tissues and organs such as the limbs, the brain, the reproductive tract and the kidney during embryognenesis (Peifer M and Polakis P, Science 2000 March. 3; 287(5458):1606-9).
Constituents of Wnt signaling pathways are expressed in embroyogenesis and act in developing and mature nervous systems (Patapoutian A, and Reichardt L F, Curr Opin Neurobiol 2000 June; 10(3):392-9). For example, Wnt signaling is involved in the initial formation of the neural plate and in subsequent patterning decisions in the embryonic nervous system, including formation of the neural crest. Wnt signaling is also required at later stages of development.
Actions of members of the Wnt signaling pathway have also been associated with disease processes. For example, Wnt signaling has been demonstrated to regulate apoptosis and may participate in degenerative processes leading to cell death in the aging brain.
In addition, inappropriate activation of the canonical Wnt signaling pathway is reported to be a major feature in human neoplasia. Oncogenic activation of this pathway can occur in several ways. For example, mutations in either APC or beta-catenin have been associated with colon carcinomas. Inappropriate expression of Wnt and Wnt binding proteins has similarly been found in a variety of human tumors. Dysregulation of the beta-catenin turnover complex has been associated with several tumor types. Thus dysregulation can include in, e.g., loss of the Adenomatous Polyposis Coli (APC) or Protein Phosphatase 2A proteins, or activating mutations of beta-catenin.
Disruption of expression of members of the Wnt signaling pathway has also been associated with apoptosis and neurological conditions such as Alzheimer's disease (De Ferrari GV, and Inestrosa NC, Brain Res Brain Res Rev 2000 August; 33(1):1-12).